Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial

Randomized Controlled Trial

doi: 10.1016/S1474-4422(12)70320-4. Epub 2013 Jan 2.

David S Knopman, Daniel I Kaufer, Murray Grossman, Chiadi Onyike, Neill Graf-Radford, Mario Mendez, Diana Kerwin, Alan Lerner, Chuang-Kuo Wu, Mary Koestler, Jill Shapira, Kathryn Sullivan, Kristen Klepac, Kristine Lipowski, Jerin Ullah, Scott Fields, Joel H Kramer, Jennifer Merrilees, John Neuhaus, M Marsel Mesulam, Bruce L Miller

Affiliations

PMID: 23290598
PMCID: PMC3756890
DOI: 10.1016/S1474-4422(12)70320-4

Randomized Controlled Trial

Adam L Boxer et al. Lancet Neurol. 2013 Feb.

Abstract

Background: Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD.

Methods: We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974.

Findings: Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI -3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, -0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one).

Interpretation: Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD.

Funding: Forest Research Institute.

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Figures

Figure 1

Patient flow diagram.

Figure 2. Primary outcome variables

(A) Change from baseline of total Neuropsychiatric Inventory (NPI) scores from the intent to treat population are shown with p values for a paired t test at each study visit. In the repeated measures analysis there was no group difference (p = 0.39). (B) Clinician’s Global Impression of Change (CGIC) values are shown at week 26 for n = 76 subjects who completed this visit. Only improved = “slightly improved (3)”, no change = “no change (4)” and Worsened = “slightly worsened (5)” are shown since no other values were recorded. Using a Mann Whitney test there was no difference in CGIC distributions (p = 0.90).

Figure 3. Functional rating scales

(A) Change from baseline Functional Activities Questionnaire (FAQ) scores in the intent to treat population. (B) Change from baseline in Clinical Dementia Rating sum of boxes (CDR-SB-FTD) scores.

Figure 4. Neuropsychological tests

(A) Change from baseline modified Boston Naming Test (BNT). (B) Change from baseline Digit Symbol Substitution Test scores.

Comment in

Hope abandoned: memantine therapy in frontotemporal dementia.
Hodges JR. Hodges JR. Lancet Neurol. 2013 Feb;12(2):121-3. doi: 10.1016/S1474-4422(13)70001-2. Epub 2013 Jan 8. Lancet Neurol. 2013. PMID: 23305744 No abstract available.

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References

1. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546–1554. - PubMed
1. Rosen HJ, Allison SC, Ogar JM, et al. Behavioral features in semantic dementia vs other forms of progressive aphasias. Neurology. 2006;67:1752–1756. - PubMed
1. Huey ED, Putnam KT, Grafman J. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology. 2006;66:17–22. - PMC - PubMed
1. Hu B, Ross L, Neuhaus J, et al. Off-Label Medication Use in Frontotemporal Dementia. American Journal Alzheimer’s Disease and Other Dementias. 2010;25:128–33. - PMC - PubMed
1. Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 2008;7:742–755. - PMC - PubMed

Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial - PubMed (original) (raw)